This supplement will further the University of Maryland Claude D. Pepper Center mission to identify factors that prevent disablement and promote enablement in older adults. To that end, a defining feature of Alzheimer?s disease (AD) and its related dementias (ADRD) is the accumulation of amyloid-beta protein in extracellular plaques within the brain and subsequent neuronal loss. Thus, the dominant hypothesis for AD pathogenesis, the ?amyloid hypothesis,? postulates that amyloid-beta accumulation is the primary event leading to AD. Most candidate treatments have targeted amyloid-beta; however, the unsuccessful trials of these treatments challenge the amyloid hypothesis and motivate the need for new intervention targets. Recent epidemiologic data also support alternative hypotheses for AD pathogenesis. Specifically, observational studies have consistently shown that AD and dementia are inversely related to cancer. This ?inverse comorbidity? may be due to pathogenesis at opposite ends of a shared biological mechanism. Two proposed mechanisms to explain inverse comorbidity between dementia and cancer are energy metabolism and inflammation. The scientific premise for these mechanisms is supported by findings that neuronal glycolysis is downregulated in AD and upregulated in cancer cells; also, higher markers of systemic inflammation are observed in persons with AD, whereas inflammatory complexes may promote or inhibit tumor growth depending on context. However, epidemiological studies of dementia and cancer have not rigorously investigated whether energy metabolism and inflammation explain this inverse comorbidity. Moreover, studies of inverse comorbidity are vulnerable to biases from selective survival because persons with cancer are more likely to die before dementia onset than persons without cancer. Limitations of current statistical methods are a key barrier to accurately quantifying the strength of inverse association between dementia and cancer and to identifying markers of biological mechanisms that may explain inverse comorbidity. Therefore, new statistical methods are needed. The specific aims of this proposal are to 1) quantify the association between incident dementia and cancer over time and 2) test the relation of metabolomic and inflammatory markers jointly with incident dementia and cancer. To achieve these goals, we will adapt and refine novel structural models for bivariate time-to-event data and apply them to harmonized archived data on over 10,000 adults aged at least 65 years enrolled in three prospective cohort studies (Health, Aging and Body Composition; Osteoporotic Fractures in Men Study; and Study of Osteoporotic Fractures). We hypothesize that even after addressing selective survival, dementia and cancer have an inverse association that is explained, in part, by markers of energy metabolism and inflammation. Novel statistical methods will provide a rigorous framework to test inverse comorbidity and will be made available to the Pepper Center network. The ultimate public health impact of this project is potential for novel candidate biomarkers to inform development of new strategies to treat or prevent AD/ADRD.